Despite the use of effective antibiotics in combination with intense cardiopulmonary support, the mortality rate from sepsis and septic shock for the last three decades has remained high (29%). During this time, the incidence of reported cases of sepsis in hospitals has more than doubled. Understanding the pathogenic mechanisms and developing new therapeutic approaches to the treatment of sepsis is necessary. One component of the research to achieve this goal is the development of animal models that accurately reproduce events encountered clinically. The primary purpose of this protocol is to develop a 96 h model of canine septic shock. This model will incorporate the conventional hemodynamic and mechanical ventilatory support utilized in human patients with septic shock including continuous sedation and analgesic treatment. This model is designed to ensure that animals will be treated similar to human septic patients that require mechanical ventilation and therefore be maintained in a semiconscious to unconscious state. This will be from the time that sepsis is initiated until the time of sacrifice. Although survival will be a primary endpoint in these studies, physiologic endpoints will provide other important measures. To obtain maximal use of these animals, blood that would be otherwise discarded will be used to perform oligonucleotide microarrays from peripheral blood mononuclear cells and proteomics from plasma. The purpose of these assays is to identify patterns of gene or protein expression which correlate with the severity of illness during sepsis and can differentiate between survivors and non-survivors. The characterization of gene and protein expression during sepsis has been a major focus of our critical care sepsis research group over the last ten years. This model has been performed in over 30 animals defining standardized treatment algorithms and survival over a range of severity of intrabronchial bacterial infections. Preliminary proteomic analysis has shown several possible correlations between protein expression and survival. These results are presently being tested to determine if they can determine survival prospectively. A manuscript describing survival, physiologic endpoints and blood analysis results in this sedated and ventilated model of sepsis is being prepared and will be sent out for peer review in the coming months.